Human papillomavirus (HPV) associated head and neck cancer is a growing public health concern. These patients commonly present at a younger age and with more advanced stage disease than patients with traditional tobacco and alcohol associated head and neck squamous cell carcinoma (HNSCC). Paradoxically, these HPV-associated tumors show notably improved survival outcomes. Mechanisms underlying these improved outcomes remain unclear. The work proposed in this Pathways to Independence Award has two primary goals: 1) to facilitate career development of the principal investigator (PI) and to help establish his independence to lead a research program investigating radiation response in virally associated cancers; and, 2) to understand how HPV-associated HNSCC differs from traditional HNSCC in response to radiation and chemotherapy. During the mentored phase of research, the PI will obtain additional training in molecular virology, human papillomavirus biology, and mouse models of cancer. The research conducted during the mentored phase will examine why HPV-associated HNSCC are more sensitive than traditional HNSCC to radiation and chemotherapy and to examine the ability of epidermal growth factor receptor (EGFR) inhibitors to sensitize HPV-associated head and neck cancer to radiation despite low levels of EGFR expression. During the independent phase, research will examine the impact of HPV viral proteins on EGFR inhibitor-mediated radiosensitization and the impact of EGFR loss on radiosensitization strategies. These studies will provide new clues regarding mechanisms of increased sensitivity to radiation and chemotherapy and may identify important new targets for therapy development to further improve outcome for patients with both HPV-associated and non-HPV-associated head and neck cancer.